tbuckley/cabot-search huggingface dataset:
Progress and prospect of technical and regulatory challenges on tissue-engineered cartilage as therapeutic combination product
Authors: Xiaolei Guo, Yuan Ma, Yue Min, Jiayi Sun, Xinli Shi, Guobiao Gao, Lei Sun, Jiadao Wang
Journal: Bioactive Materials (2022)

Hyaline cartilage plays a critical role in maintaining joint function and pain. However, the lack of blood supply, nerves, and lymphatic vessels greatly limited the self-repair and regeneration of damaged cartilage, giving rise to various tricky issues in medicine. In the past 30 years, numerous treatment techniques and commercial products have been developed and practiced in the clinic for promoting defected cartilage repair and regeneration. Here, the current therapies and their relevant advantages and disadvantages will be summarized, particularly the tissue engineering strategies. Furthermore, the fabrication of tissue-engineered cartilage under research or in the clinic was discussed based on the traid of tissue engineering, that is the materials, seed cells, and bioactive factors. Finally, the commercialized cartilage repair products were listed and the regulatory issues and challenges of tissue-engineered cartilage repair products and clinical application would be reviewed.
The role of NURR1 in metabolic abnormalities of Parkinson’s disease
Authors: Murad Al-Nusaif, Yuting Yang, Song Li, Cheng Cheng, Weidong Le
Journal: Molecular Neurodegeneration (2022)

A constant metabolism and energy supply are crucial to all organs, particularly the brain. Age-dependent neurodegenerative diseases, such as Parkinson's disease (PD), are associated with alterations in cellular metabolism. These changes have been recognized as a novel hot topic that may provide new insights to help identify risk in the pre-symptomatic phase of the disease, understand disease pathogenesis, track disease progression, and determine critical endpoints. Nuclear receptor-related factor 1 (NURR1), an orphan member of the nuclear receptor superfamily of transcription factors, is a major risk factor in the pathogenesis of PD, and changes in NURR1 expression can have a detrimental effect on cellular metabolism. In this review, we discuss recent evidence that suggests a vital role of NURR1 in dopaminergic (DAergic) neuron development and the pathogenesis of PD. The association between NURR1 and cellular metabolic abnormalities and its implications for PD therapy have been further highlighted.
Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure
Authors: Justin M. Vader, Michael M. Givertz, Randall C. Starling, Steven E. McNulty, Kevin J. Anstrom, Patrice Desvigne-Nickens, Adrian F. Hernandez, Eugene Braunwald, Douglas L. Mann
Journal: JACC Heart Failure (2022)
OP0037 USE OF PRIMARY HEALTHCARE AND RADIOLOGICAL IMAGING PRECEDING A DIAGNOSIS OF RHEUMATOID ARTHRITIS: A DANISH NATIONWIDE COHORT STUDY
Authors: A. De Thurah, H. Jensen, T. Maribo, M. Bach Jensen, A. Sandbæk, E. M. Hauge, L. A Rasmussen
Journal: Annals of the Rheumatic Diseases (2022)

Background Focus on early diagnosis and treatment initiation is key in rheumatoid arthritis (RA) to prevent permanent joint damage and systemic manifestations. Increased use of healthcare services before an RA diagnosis can be seen as a proxy for symptom presentation and the actions taken by healthcare professionals, and thus indicate an opportunity for earlier diagnosis. However, little is known about where and when people use healthcare services before an RA diagnosis. Objectives To explore the pattern in use of healthcare services during the 12 months preceding a diagnosis of RA in Denmark. Methods We conducted a population-based cohort study using data from Danish national registries. For every patient diagnosed with RA in 2014-2018 we matched ten reference persons from the Danish general population without RA, listed in the same general practice and with same age and sex. Healthcare use was defined as: daytime face to face contacts to general practice, contacts to private practicing physiotherapists. We estimated the monthly healthcare use for patients with RA and reference persons in the 12 months preceding the diagnosis, and we compared their healthcare use by incidence rate ratios (IRR) for each month, adjusted for sociodemographic characteristics and comorbidity. Results 7,427 patients with RA and 74,270 reference persons were included in the study. The median age was 62 years (interquartile interval (IQI): 51-71), and 65% were women. Patients with RA had an average of 0.5 contacts per month in general practice from 12 months until six months prior to the diagnosis (Figure 1); this number increased from six months before the diagnosis to an average of one contact in the last month before the diagnosis. Reference persons had an average of 0.4 contacts per months throughout the entire study period. Compared to their references, patients with RA had statistically significantly more contacts during all 12 months before the diagnosis date; IRR increased from 1.25 (95% CI: 1.19-1.30) to 2.63 (2.55-2.71) during the study period. Patients with RA also had statstistically significantly more contacts to physiotherapists compared to their references throughout the entire study period, and increasing contact rates from eight months before the diagnosis. This was primarily driven by more contacts in women with RA compared to their references. Conclusion Patients with RA had more contacts to general practice and physiotherapists in all 12 months preceding the RA diagnosis compared to references and these contact rates increased further the last six to eight months in patients with RA. This indicates symptom presentation for several months before the RA is diagnosed, and it indicates that a window of opportunity exists to expedite referral to specialist care and the diagnosis of RA. Disclosure of Interests None declared.
OP0049 FURTHER CHARACTERIZATION OF CLINICAL AND LABORATORY FEATURES OCCURRING IN VEXAS SYNDROME IN A LARGE-SCALE ANALYSIS OF MULTICENTER CASE-SERIES OF 116 FRENCH PATIENTS
Authors: S. Georgin-Lavialle, B. Terrier, K. Olivier, A. Mekinian
Journal: Annals of the Rheumatic Diseases (2022)

<h3>Background</h3> A new autoinflammatory syndrome related to somatic mutations of <i>UBA1</i> was recently described and called VEXAS syndrome. <h3>Objectives</h3> To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. <h3>Methods</h3> Case-series. Patients referred to a French multicenter registry between November 2020 and May 2021. 116 patients with VEXAS syndrome. Frequency and median of parameters and vital status, from diagnosis to the end of the follow-up. <h3>Results</h3> Main clinical features were skin lesions (83.5%), non-infectious fever (63.6%), weight loss (62%), lung involvement (49.6%), ocular symptoms (38.8%), relapsing chondritis (36.4%), venous thrombosis (34.7%), lymph nodes (33.9%), and arthralgia (27.3%). Hematological disease was present in 58 cases (50%), considered as myelodysplastic syndrome (MDS, n= 58) and monoclonal gammapathy of unknown significance (n=12).<i>UBA1</i> mutations included p.M41T (44.8%), p.M41V (30.2%), p.M41L (18.1%), and splice mutations (6.9%). After a median follow-up of 3.0 years, 18 patients died (15.5%), from infectious origin (n=9) and MDS progression (n=3). Unsupervised analysis identified 3 clusters: cluster 1 (47%) with mild-to-moderate disease; cluster 2 (16%) with underlying MDS and higher mortality rates; cluster 3 (37%) with constitutional manifestations, higher C-reactive protein levels and less frequent chondritis. Five-year probability of survival was 84.2% in cluster 1, 50.5 % in cluster 2, and 89.6% in cluster 3. <i>UBA1</i> p.Met41Leu mutation was associated with a better prognosis. <h3>Conclusion</h3> VEXAS syndrome displays a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified <i>UBA1</i> mutation. <h3>Disclosure of Interests</h3> None declared.
Differential IL-12 signaling induces human natural killer cell activating receptor-mediated ligand-specific expansion
Authors: Avishai Shemesh, Harry Pickering, Kole T. Roybal, Lewis L. Lanier
Journal: The Journal of Experimental Medicine (2022)

IL-12 is an essential cytokine involved in the generation of memory or memory-like NK cells. Mouse cytomegalovirus infection triggers NK receptor-induced, ligand-specific IL-12-dependent NK cell expansion, yet specific IL-12 stimulation ex vivo leading to NK cell proliferation and expansion is not established. Here, we show that IL-12 alone can sustain human primary NK cell survival without providing IL-2 or IL-15 but was insufficient to promote human NK cell proliferation. IL-12 signaling analysis revealed STAT5 phosphorylation and weak mTOR activation, which was enhanced by activating NK receptor upregulation and crosslinking leading to STAT5-dependent, rapamycin-sensitive, or TGFβ-sensitive NK cell IL-12-dependent expansion, independently of IL-12 receptor upregulation. Prolonged IL-2 culture did not impair IL-12-dependent ligand-specific NK cell expansion. These findings demonstrate that activating NK receptor stimulation promotes differential IL-12 signaling, leading to human NK cell expansion, and suggest adopting strategies to provide IL-12 signaling in vivo for ligand-specific IL-2-primed NK cell-based therapies.
Potential IL2 Substitute Shrinks Solid Tumors
Journal: Cancer Discovery (2022)

Nemvaleukin alfa, an engineered cytokine that may induce the tumor-fighting benefits of IL2 without the side effects, has demonstrated effectiveness against solid tumors. As a monotherapy, the drug produced overall response rates of 13% in patients with advanced melanoma and 18.2% in advanced renal cell carcinoma. When combined with pembrolizumab, the drug produced responses in 16.1% of patients with various solid tumor types.
Chest-Wall Adipose Tissue Excisional Biopsy During Pacemaker or Defibrillator Implantation
Authors: Chi Zhang, Daniel R. Musikantow, Daniel N. Pugliese, Sumeet S. Mitter, Jacob Koruth, Noah Moss, Donna M. Mancini, Srinivas R. Dukkipati, Vivek Y. Reddy, Marc A. Miller
Journal: Journal of the American College of Cardiology (2022)
OP0036 CLINICALLY SUSPECT ARTHRALGIA PATIENTS WITH A LOW LEVEL OF EDUCATIONAL ATTAINMENT HAVE AN INCREASED RISK TO DEVELOP INFLAMMATORY ARTHRITIS
Authors: S. Khidir, E. Van Mulligen, A. Van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2022)

Background Cross-sectional studies on educational levels have shown that inflammatory arthritis (IA) and rheumatoid arthritis (RA) are more prevalent among people with a lower educational attainment. Studies on educational attainment in individuals at risk for RA could shed light on the influence of socioeconomic factors on RA development, which is divided in an asymptomatic and symptomatic pre-RA stage. To our knowledge, longitudinal studies on educational attainment and IA-development in symptomatic individuals at risk of RA are lacking. Objectives To determine the association between educational attainment and progression from clinically suspect arthralgia to IA and to perform mediation analysis to elucidate pathways. Methods 600 consecutive patients presenting with clinically suspect arthralgia were followed for the development of IA, identified at joint examination by rheumatologists during median follow-up of 25 months. Educational attainment was defined as low (lower general secondary education), medium, or high (college or university education). Contrast enhanced 1.5T MRI of hand and foot were made at baseline and were evaluated for synovitis/tenosynovitis/osteitis, according to the method of rheumatoid arthritis MRI scoring system (RAMRIS) and Havaardsholm. Association between educational attainment and IA-development was studied with cox-regression analysis. To evaluate if subclinical joint inflammation is intermediary in the path of educational attainment and IA-development, a three-step mediation analysis was performed, before and after correction for age. Results Patients with a low level of educational attainment were older, had a higher BMI, and smoked more often compared to patients with a high educational level. Low educational attainment was associated with increased IA-development (HR=2.5, 95%CI=1.4-4.7. p=0.003; see Figure 1), also after correction for age, BMI and smoking-status (HR=2.1, 95%CI=1.03-4.4, p=0.041). Moreover, patients with a lower educational level had higher levels of subclinical inflammation at presentation, which associated with a higher risk of progression to IA. Mediation analyses revealed that the association between low educational attainment and IA-development reduced when adding the level of subclinical inflammation (HR=1.8, 95%CI=0.9-3.5, p=0.073), suggesting that the association between educational attainment and IA-development is partly mediated by higher levels of subclinical inflammation. Mediation analysis with age correction provided similar results. Conclusion This is the first evidence that lower educational attainment of patients with arthralgia is associated with a higher risk of developing arthritis. This is partly caused by more severe subclinical joint inflammation. Further research into the role of socioeconomic factors on the development of RA is warranted. Disclosure of Interests None declared.
Aberrant expansion of spontaneous splenic germinal centers induced by hallmark genetic lesions of aggressive lymphoma
Authors: Grace M. Pindzola, Raud Razzaghi, Rachel N. Tavory, Hang T. Nguyen, Vivian M. Morris, Moyi Li, Shreya Agarwal, Bonnie Huang, Takaharu Okada, Hans C. Reinhardt, Gero Knittel, Hamid Kashkar, Ryan M. Young, Stefania Pittaluga, Jagan R. Muppidi
Journal: Blood (2022)
35 years of discussions with Prof. Maeda on the EPR effect and future directions
Authors: Yasuhiro Matsumura
Journal: Journal of Controlled Release (2022)

In May 2021, 35 years after first announcing the enhanced permeability and retention (EPR) effect, Dr. Maeda passed away. As a theoretical pillar of high molecular weight drug delivery systems (DDS) with high biocompatibility, the EPR effect has been proven worldwide in experimental mouse models. However, in clinical solid tumors, awareness of the EPR effect is insufficient, and more importantly, DDS has not become the mainstream cancer treatment. Both Dr. Maeda and I were acutely aware of this, and for 35 years, we discussed what to do about it and strived to make up for the inadequacies of the EPR effect by employing different strategies. Dr. Maeda came up with ways to use tumor vascular permeability more effectively and to apply oxidative stress to tumor cells. I proposed cancer stromal targeting (CAST) therapy using the anti-insoluble fibrin antibody conjugated with an anticancer agent in order to overcome the insufficiency of the EPR effect in clinical solid cancers, which possess abundant stromal tissue. Clinical cancers are surrounded by an abundant stroma and survive even under hypoxia and malnutrition due to this stromal barrier. Cancer cells become resistant to any external attack, including with anticancer drugs and radiation. While it goes without saying that EPR effects are important in clinical solid cancer strategies, DDSs that offer both accumulation and even distribution in solid cancers are also required.
OP0184 PREVALENCE OF SUBCLINICAL GIANT CELL ARTERITIS IN PATIENTS WITH POLYMYALGIA RHEUMATICA
Authors: E. de Miguel, P. Macchioni, E. Conticini, C. Campochiaro, R. Karalilova, S. Monti, C. Ponte, G. Klinowski, I. Monjo, P. Falsetti, A. Tomelleri, Z. Batalov, A. Hocevar
Journal: Annals of the Rheumatic Diseases (2022)

Background Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are closely related diseases. PMR occurs in approximately 50 % of patients with GCA 1 ; however the prevalence of subclinical GCA in PMR has not yet been widely studied. Objectives The aim of our multicenter, prospective study was to determine the prevalence of subclinical GCA in newly diagnosed PMR, using vascular ultrasound (US) as a diagnostic tool. Methods Eight European centers participated in the study. The studied cohort represented consecutive newly diagnosed patients with PMR who fulfilled 2012 EULAR/ACR Provisional Classification Criteria for Polymyalgia Rheumatica 2 without symptoms or signs suggestive for GCA. All patients underwent ultrasound (US) of both hips and shoulders, as well as of four bilateral arterial territories (i.e. temporal, common carotid, subclavian and axillary arteries). Patients with positive halo signs were considered to have subclinical GCA 3 . An intima-media thickness ≥0.34 mm for frontal and parietal TA, 0.42mm for common TA, and ≥1 mm for common carotid, axillary and subclavian arteries for positive result. Clinical demographic and laboratory characteristics of the PMR pure group were compared with the PMR/GCA patient group. Results A total of 258 patients were included, 137 (53.1%) females with a mean age of 73±8.4 years. Table 1 shows the main differences in PMR patients with and without subclinical GCA. The only statistical significant difference between the two groups was the higher prevalence of morning stiffness &gt; 40 minutes in the pure PMR group (p&lt;0.05). A halo sign was found on at least one of the examined arteries in 56/258 patients (21.7%). The different subtypes of vessel involvement were available in 216 cases. Data compatible with the diagnosis of GCA was found in 41 cases (19%): 10 (24.3%) had only temporal artery involvement (“cranial” GCA), 27 (65.8%) had an extra-cranial artery involvement and 4 (9.8%) a mixed form with both cranial and extra-cranial artery involvement (Figure 1). Table 1. Clinical and demographic characteristics Figure 1. Subtypes of subclinical GCA in PMR in 216 patients with cranial and extra-cranial examination Conclusion One fifth of PMR patients without symptoms or signs of GCA have ultrasound findings consistent with the diagnosis of GCA. Subclinical GCA in PMR shows a predilection for extra-cranial artery involvement. References [1]Buttgereit F et al. JAMA. 2016;315:2442-58. [2]Dasgupta B et al. Arthritis &amp; Rheumatism. 2012; 64:943–954. [3]De Miguel E et al. Rheumatology 2018; 57:318-321. Acknowledgements To the GCA/PMR study group Disclosure of Interests None declared
OP0007-HPR AN EPIDEMIOLOGICAL STUDY OF FOOT AND ANKLE PAIN AND HEALTH-RELATED JOB LOSS IN ADULTS OVER 50: CROSS-SECTIONAL FINDINGS FROM THE HEAF COHORT
Authors: D. Jobanputra, L. Cherry, K. Walker-Bone, C. Price, S. D’angelo, G. Ntani
Journal: Annals of the Rheumatic Diseases (2022)

Background Foot and ankle pain (FAP), particularly that of musculoskeletal origin, is increasingly prevalent in our aging populations 1 . Moreover, governments need people to work to older ages to reduce the costs of pensions and welfare benefits. It is not currently known however whether people with FAP are able to keep working or to what extent it pushes people out of work. We investigated this question in older working adults. Objectives To determine whether FAP is associated with HRJL amongst older working adults. Methods Health And Employment After Fifty 2 is a longitudinal population-based cohort incepted 2013 to investigate health and retirement. At follow-up two years later, people were asked to complete a full-body mannequin which included the ankles/feet. Mannequins were coded: foot/ankle pain (FAP) with pain at other sites; pain elsewhere but not FAP; and no pain. Two years later, participants were asked whether they had left paid work entirely or partly because of health (Health-related job loss (HRJL). A Cox proportional hazards model was used to explore associations between health-related job loss, FAP, and other potential risk factors (such as age, mental health, BMI, and finances). A sensitivity analysis was carried out to determine which occupational activities were significantly associated with health-related job loss due to FAP. Results At 2 years, 4050 participants completed a pain mannequin, amongst whom 3762 were in paid work. Over 2 further years of follow-up, there were 235 incident HRJLs. Amongst those with HRJL, 73 had no pain, 54 had pain involving FAP, 108 had pain not involving FAP. After adjusting for age and sex, people with FAP had 83% increased risk of HRJL compared to people with no pain (HR=1.83, 95% CI 1.29-2.61), whilst those with pain NOT involving FAP had 34% increased risk (HR1.34, 95% CI 1.00 – 1.80). FAP remained a significant predictor of HRJL within a fully adjusted model (HR=1.65, 95% CI 1.15-2.36). Sensitivity analyses confirmed that doing jobs which involved climbing more than 30 flights of stairs was associated with increased risk of HRJL amongst people with FAP (HR=1.96, 95% CI 1.00-3.80). Conclusion FAP is a risk factor for HRJL amongst older working adults, particularly if their job involves stair climbing. Potentially, modification of duties to reduce stair climbing could mitigate job loss amongst people with FAP. References [1]Executive HaS. Work-related ill health and occupational disease . https://www.hse.gov.uk/statistics/causdis/; 2020. [2]Keith T. Palmer KW-B, E. Clare Harris, Cathy Linaker, Stefania D’ANgelo, Avan Aihi Sayer, Catharine R. Gale, Maria Evandrou, Tjeerd van Staa, Cyrus Cooper, David Coggon. Health and Employment after Fifty (HEAF): a new prospective cohort study. BMC Public Health 2015. Disclosure of Interests None declared.
Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways
Authors: Yi Qin, Ming-Long Cai, Hui-Zhi Jin, Wei Huang, Chen Zhu, Aline Bozec, Jingang Huang, Zhu Chen
Journal: Annals of the Rheumatic Diseases (2022)

Age-associated B cells (ABCs) are a recently identified B cell subset, whose expansion has been increasingly linked to the pathogenesis of autoimmune disorders. This study aimed to investigate whether ABCs are involved in the pathogenesis and underlying mechanisms of rheumatoid arthritis (RA).ABCs were assessed in collagen-induced arthritis (CIA) mice and patients with RA using flow cytometry. Transcriptomic features of RA ABCs were explored using RNA-seq. Primary fibroblast-like synoviocytes (FLS) derived from the synovial tissue of patients with RA were cocultured with ABCs or ABCs-conditioned medium (ABCsCM). IL-6, MMP-1, MMP-3 and MMP-13 levels in the coculture supernatant were detected by ELISA. Signalling pathways related to ABCs-induced FLS activation were examined using western blotting.Increased ABCs levels in the blood, spleen and inflammatory joints of CIA mice were observed. Notably, ABCs were elevated in the blood, synovial fluid and synovial tissue of patients with RA and positively correlated with disease activity. RNA-seq revealed upregulated chemotaxis-related genes in RA ABCs compared with those in naive and memory B cells. Coculture of FLS with RA ABCs or ABCsCM led to an active phenotype of FLS, with increased production of IL-6, MMP-1, MMP-3 and MMP-13. Mechanistically, ABCsCM-derived TNF-α promoted the upregulation of interferon-stimulated genes in FLS, with elevated phosphorylation of ERK1/2 and STAT1. Furthermore, blockage of ERK1/2 and Janus Kinase (JAK)-STAT1 pathways inhibited the activation of FLS induced by ABCsCM.Our results suggest that ABCs contribute to the pathogenesis of RA by inducing the activation of FLS via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways.